PSC and genetics Tom Hemming Karlsen Research Institute of Internal Medicine & Department of Transplantation Medicine University of Oslo & Oslo University Hospital, Norway New Haven – June 25th 2016

ous-research.no/nopsc www.ipscsg.org

Liver transplantation in Norway (Fosby et al., 2015)

Primary sclerosing cholangitis

Primary sclerosing cholangitis

IBD prevalence in PSC - geography

IBD prevalence in PSC - geography (Tanaka et al., 2014)

«Unknown» PSC patients ♀ 71% PSC prevalence in IBD Known PSC prevalence 2.2% True PSC prevalence 8.1% UC 6.8%, CD 9.1% «Unknown» PSC patients ♀ 71% (Lunder et al., Gastroenterology early online)

(Gou et al., in submission) PSC-IBD (Gou et al., in submission)

GWAS examples - drug-induced liver injury Flucloxacillin Lumiracoxib Amoxicillin-clavulunate (For references to studies, see https://www.genome.gov/26525384)

GWAS examples – AIH, PBC and PSC Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis (For references to studies, see https://www.genome.gov/26525384)

«GWAS genetics» Additional impact from unexplained (or “missing”) heritability Additional impact from environmental factors (Bach, 2002)

The HLA associations in PSC

A fundamental biological problem

HLA associations and the antigen

(Ellinghaus et al., Nature Genetics 2016) Genetics and the gut (Ellinghaus et al., Nature Genetics 2016)

The gut microbiome FUT2 PCA (Wacklin et al. 2011) (Kummen et al, Gut 2016)

The gut-liver relationship in PSC

The magnitude of non-genetic factors (Wang et al., in revisions)

The magnitude of genetic factors (Wang et al., in revisions)

The gut microbiota in PSC (Karlsen, in press Gut)

Other non-HLA genes

Genome-wide significant risk genes Locus Chr. lead SNP Gene Study (year) 1 rs3748816 MMEL1, TNFRSF14 Folseraas et al. 2012 2 rs6720394 BCL2L11 Melum et al. 2011 3 rs7426056 CD28, CTLA4 Liu et al. 2013 4 rs7556897 CCL20 Ellinghaus et al. 2016 5 rs3749171 GPR35 Ellinghaus et al. 2013 6 rs3197999 MST1 7 rs3774937 NFKB1 8 rs13140464 IL2, IL21 9 rs56258221 BACH2 10 rs4147359 IL2RA Srivastava et al. 2012 11 rs7937682 SIK2 12 rs11168249 HDAC7 13 rs12369214 RFX4, RIC8B 14 rs3184504 SH2B3, ATXN2 15 16 rs11649613 CLEC16A, SOCS1 18 rs1452787 TCF4 17 rs1788097 CD226 19 rs60652743 PRKD2, STRN4 21 rs2836883 PSMG1

Independently reported risk genes Locus Chr. lead SNP Gene Study (year) 1 rs3748816 MMEL1, TNFRSF14 Folseraas et al. 2012 2 rs6720394 BCL2L11 Melum et al. 2011 3 rs7426056 CD28, CTLA4 Liu et al. 2013 4 rs7556897 CCL20 Ellinghaus et al. 2016 5 rs3749171 GPR35 Ellinghaus et al. 2013 6 rs3197999 MST1 7 rs3774937 NFKB1 8 rs13140464 IL2, IL21 9 rs56258221 BACH2 10 rs4147359 IL2RA Srivastava et al. 2012 11 rs7937682 SIK2 12 rs11168249 HDAC7 13 rs12369214 RFX4, RIC8B 14 rs3184504 SH2B3, ATXN2 15 16 rs11649613 CLEC16A, SOCS1 18 rs1452787 TCF4 17 rs1788097 CD226 19 rs60652743 PRKD2, STRN4 21 rs2836883 PSMG1

Hypothesis-free → hypothesis-driven

Familial PSC variants

(Yiang et al., in preparation) Familial PSC (Yiang et al., in preparation)

Modifier genes

Modifier genes (Alberts et al, EASL 2016)

Cholangiocarcinoma genetics

Cholangiocarcinoma genetics Chromosome Frequency (%) Potential therapeutics for further study KRAS ch12 38% Refametinib (phase II in HCC) CDKN2A chr9 20% Ilorasertib (phase II in solid tumors) SMAD4 chr18 18% TGFβ receptor inhibitor (phase I, i.e. LY2157299 (Galunisertib)) ERBB2 chr17 8% Trastuzumab, Pertuzumab BRAF V600 chr7 6% Vemurafenib, Encorafenib EGFR Gefitinib, Erlotinib, Afatinib, (Cetuximab) TGFBR2 chr3 2% TGFβ receptor inhibitor FGF23 chr12 FGFR4 inhibitor (phase I, i.e. BLU-554, FGF401) FGFR2 chr10 BGJ398 (phase II study), PIK3CA 4% Everolimus (RAD001) Total 66% (patients with one or more „druggable“ targets) (Goeppert et al, EASL 2016)

Concluding statements ~30 risk genes, specific interactions with environment Familial PSC is rare, consider if ≥3 affected and no IBD Genetics in risk stratification currently being explored Encouraging first findings in CCA sequencing project